RESUMEN
The aim of this study was to investigate the postmortem redistribution of several drugs in a rat model and to examine if any of the pharmacological properties was related to the extent of this phenomenon. One of the following drugs: phenobarbital (phenobarbitone), acetaminophen (paracetamol), carbamazepine, codeine, verapamil, amphetamine, mianserin, trimeprazine (alimemazine) or chloroquine was administered together with nortriptyline orally to rats 90 min prior to sacrifice. Heart blood was sampled immediately before sacrifice and after 2 h postmortem, as it has previously been shown that this is sufficient time for postmortem concentration changes to occur in heart blood. Blood was also sampled from the clamped abdominal inferior vena cava (representing peripheral blood) and tissue samples were taken from lungs, myocardium, liver, kidney, thigh muscle, forebrain, and vitreous humor together with a specimen from the minced carcass. Drugs were analyzed by high performance liquid or gas chromatography. For phenobarbital, acetaminophen and carbamazepine the postmortem to antemortem blood drug concentration ratios were close to 1.0 and tissue concentrations were low. The postmortem to antemortem heart blood drug concentration ratio for chloroquine (6.9 +/- 1.5) was higher than for nortriptyline (3.5 +/- 0.3), and the remaining drugs (codeine, verapamil, amphetamine, mianserin, and trimeprazine) showed ratios of the same magnitude as nortriptyline. The postmortem to antemortem blood drug concentration ratios for both heart blood and blood from the vena cava and also the lung to antemortem blood drug concentration ratio were closely related to the apparent volume of distribution for the drugs studied (p < 0.001). Accordingly, an apparent volume of distribution of more than 3-4 L/kg is a good predictor that a drug is liable to undergo postmortem redistribution with significant increments in blood levels. The postmortem drug concentration in blood from vena cava was closely related to the antemortem blood level, confirming that among the postmortem samples, the peripheral blood sample was the most representative for the antemortem blood concentration.
Asunto(s)
Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Cambios Post Mortem , Animales , Medicina Legal/métodos , Masculino , Ratas , Ratas Wistar , Distribución TisularRESUMEN
The National Institute of Forensic Toxicology (NIFT) in Oslo receives blood samples from all Norwegian drivers suspected of driving under the influence of alcohol. It is well known that a large proportion of the arrested drunken drivers are repeat offenders. The purposes of this investigation was to find the arrest rates (the percentage of subjects arrested once or more) among drunken drivers followed retrospectively and prospectively during the 11-year period 1984-1994 and the probability of 'abstaining' from becoming a recidivist during the 9 years subsequent to the year of selection. By examining the rearrest rates during the 3 following years for drivers selected in 1986, 1989, 1991 and 1992 we tried to look for major effects due to the change in the Norwegian road traffic act of 1988. Altogether 45% of the selected drunken drivers were arrested two or more times. Totally the '9-year survival rate' (i.e. not being rearrested) was 60% for drivers with blood alcohol concentration (BAC) selected from the interval 0.06-0.09%; 56% from BAC 0.13-0.16% and 51% from 0.26-0.29%. The data were further evaluated with respect to frequency of rearrest during 3 years after selection, and was around 30% in 1986, while it was lower for drivers selected in 1992 (19%). An explanation for the reduction in rearrest rate may be the changes in the road traffic act which took place in 1988.
Asunto(s)
Consumo de Bebidas Alcohólicas/epidemiología , Conducción de Automóvil/estadística & datos numéricos , Crimen/estadística & datos numéricos , Adolescente , Adulto , Anciano , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/legislación & jurisprudencia , Consumo de Bebidas Alcohólicas/tendencias , Conducción de Automóvil/legislación & jurisprudencia , Etanol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Vigilancia de la Población , Estudios Prospectivos , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
In this study we have evaluated the postmortem pharmacokinetics of amitriptyline (Ami) and metabolites in pigs after oral and intravenous administration, and the results are compared with previous studies in rats and humans. In addition a meticulous investigation of blood and tissue concentrations after postmortem intravenous infusion of Ami was undertaken. Of a total of 9 over-night fasted pigs, 3 were given 25 mg/Kg Ami orally, and another 3 pigs received an intravenous infusion lasting 1 h of 3.3 mg/Kg Ami prior to death. The final 3 pigs were sacrificed and then given the intravenous infusion after death. After approximately 5 h at room temperature, all carcasses were subsequently stored at 4-5 degrees C. Postmortem blood samples were collected at 0.25, 1, 2, 4, 8, 24, 48, and 96 h through an indwelling intracardial needle. Postmortem examination with blood and tissue sampling was performed 96 h after death. Analysis was carried out by high performance liquid chromatography with ultraviolet detection. Postmortem blood samples from the heart of the orally dosed animals revealed large and variable concentration increases of 99(30-243)% for Ami and 96(52-429)% for the main metabolite 10-OH-Ami at 96 h. In the intravenously infused live pigs heart blood Ami increased by 55(33-69)% and 10-OH-Ami increased by 232(76-240)%. Blood from the atria had significantly higher Ami concentrations than blood from both ventricles in the animals dosed while alive, and the drug concentration in femoral blood was higher than in heart blood (p < 0.01). In the orally dosed pigs the left lobe of the liver had significantly higher Ami levels than the right lobe. Tissue/blood Ami concentration ratios were generally lower than previously reported in rats and approximating the levels reported in humans. The animals infused intravenously after death demonstrated high drug levels in blood samples from central vessels, heart, lungs as well as cerebrospinal fluid and vitreous humour. This implies that the presence of a lethal concentration of a drug in just one sample of heart blood can prove worthless in a case where agonal drug infusion may have occurred.
Asunto(s)
Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Cambios Post Mortem , Porcinos/metabolismo , Administración Oral , Amitriptilina/administración & dosificación , Animales , Antidepresivos Tricíclicos/administración & dosificación , Cromatografía Líquida de Alta Presión , Humanos , Infusiones Intravenosas , Ratas , Distribución TisularRESUMEN
Hepatic cytochrome P-450 enzymes mediate at least two important biotransformation pathways of codeine and ethylmorphine starting with either N-demethylation or O-dealkylation, producing polar metabolites which are then subsequently glucuronidated. The present study was designed to characterise the acute effects of ethanol on the metabolism of ethylmorphine and to compare it with the effects on codeine in suspensions of freshly isolated rat hepatocytes. Isolated rat hepatocytes from male Wistar rats were prepared by a collagenase perfusion method. Ethylmorphine, codeine and their metabolites were quantified by HPLC with UV detection. The total ethylmorphine elimination rate was reduced by 12% at 5mM and 38% at 100 mM ethanol. The corresponding percentages for codeine were 16 and 43%. In the presence of ethanol the concentrations of several intermediate and end products of ethylmorphine and codeine changed markedly from the control situation. The experimental data were applied to a mathematical compartmental linear model to estimate the influence of ethanol on the separate reaction rates in the two main metabolic pathways. The ratios between reaction rate constants in the ethylmorphine experiments at 100 and 0 mM ethanol were 0.65 for ethylmorphine-->norethylmorphine, 0.63 for norethylmorphine-->normorphine, 0.56 for ethylmorphine-->morphine, 0.49 for morphine-->normorphine, 0.31 for normorphine-->normorphine-3-glucuronide and 0.49 for morphine-->morphine-3-glucuronide. Almost similar effects of ethanol on codeine metabolism were found. In additional experiments, norethylmorphine or norcodeine (50 microM) was incubated with 5 mM to 100 mM of ethanol and the metabolism of both norethylmorphine and norcodeine was found to be inhibited by ethanol in a concentration-dependent manner. The glucuronidation of morphine and normorphine added in separate experiments was also inhibited by ethanol, from 22 to 36% for morphine-3-glucuronide and 30 to 60% for normorphine-3-glucuronide, respectively, in the presence of 5 mM to 100 mM of ethanol. It was concluded that all steps in the metabolism of ethylmorphine (and codeine) leading to the end products morphine-3-glucuronide and normorphine-3-glucuronide were inhibited by ethanol, and that the glucuronidation process were the ones most affected by ethanol.
Asunto(s)
Etanol/farmacología , Etilmorfina/metabolismo , Hígado/metabolismo , Animales , Codeína/metabolismo , Etilmorfina/farmacocinética , Glucuronatos/metabolismo , Técnicas In Vitro , Hígado/citología , Masculino , Modelos Biológicos , Morfina/metabolismo , Ratas , Ratas WistarRESUMEN
The purpose of the present study was to investigate the role of specific CYPs responsible for the O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M), as well as that of norethylmorphine (NEM) and norcodeine (NCD) to normorphine (NM) in rat liver microsomes. Liver microsomes metabolize EM and CD to M, and NEM and NCD to NM, in the presence of an NADPH-generating system. The metabolites of EM and CD were determined by HPLC with UV and electrochemical detection. In the present study, the role of CYP2D1 in O-dealkylation of EM/NEM and CD/NCD was investigated by use of specific antiCYP antibodies. When testing rabbit antirat CYP2D1, 2E1, 2C11, and 3A2 antibodies, only the antiCYP2D1 antibody inhibited the EM/NEM and CD/NCD O-dealkylase activities significantly. The maximum inhibition achieved was approximately 80% at a protein ratio (IgG to microsomes) of 10:1, p = 0.001. The contribution of CYP2D1 to the O-dealkylation of EM/NEM and CD/NCD was further confirmed by use of the specific CYP2D1 inhibitors quinine and propafenone. Five microM of quinine inhibited the EM/NEM and CD/NCD O-dealkylase activities by approximately 80%. The CYP3A inhibitor troleandomycin (TAO) failed to inhibit the CYP2D1 catalyzed reaction, but did inhibit the N-demethylation of EM and CD. The O-dealkylation of NEM and NCD was also impaired in Dark Agouti rat (DA) liver microsomes. Taken together, the immunoinhibition and chemical-inhibitor studies of rat liver microsomes provided convincing evidence for the involvement of CYP2D1, the rat counterpart of human CYP2D6, in the metabolism of EM/NEM and CD/NCD to the corresponding O-dealkylated metabolites.
Asunto(s)
Codeína/metabolismo , Citocromo P-450 CYP2D6/fisiología , Etilmorfina/metabolismo , Microsomas Hepáticos/metabolismo , Narcóticos/metabolismo , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Remoción de Radical Alquila , Femenino , Masculino , Conejos , Ratas , Ratas WistarRESUMEN
1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration.
Asunto(s)
Etilmorfina/farmacocinética , Adulto , Biotransformación , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Esquema de Medicación , Etilmorfina/administración & dosificación , Etilmorfina/efectos adversos , Genotipo , Glucuronatos/metabolismo , Humanos , Masculino , Morfina/metabolismoRESUMEN
The O-dealkylation of ethylmorphine (EM) and codeine (CD) to morphine (M) co-segregates with debrisoquine/sparteine genetic polymorphism in man. CD O-demethylation is catalysed by cytochrome P450 2D1 (CYP2D1) in rats. In the present study, the O-deethylation of EM was examined and compared with that of CD in suspensions of freshly-isolated hepatocytes prepared by a collagenase method from Wistar rats with and without CYP2D1 inhibitors. Isolated hepatocytes were also prepared from Dark Agouti (DA) rats deficient in CYP2D1, and were incubated with EM or CD. EM, CD and their metabolites were quantified by HPLC with UV detection. EM had a similar pattern of metabolism to that of CD in suspensions of hepatocytes from Wistar rats. Both EM and CD were O-dealkylated to form M plus morphine-3-glucuronide (M3G) and N-demethylated to form norethylmorphine (NEM) or norcodeine (NCD), respectively, which were further metabolized to normorphine (NM) and finally glucuronidated to normorphine-3-glucuronide (NM3G). As compared to hepatocytes from Wistar rats, DA rats were characterized by a markedly decreased formation (70 approximately 75% reduction) of M plus M3G from both EM and CD. Quinine, quinidine, propafenone and sparteine all inhibited EM O-deethylation as well as CD O-demethylation. Quinine was the most potent inhibitor of both these O-dealkylations (Ki = 0.2 microM for both EM and CD, respectively). Quinine as well as the other inhibitors inhibited both EM and CD O-dealkylation competitively and with small differences in Ki versus EM and CD, respectively. The metabolism of EM to M plus M3G and that of CD to M plus M3G was highly correlated when results from the various separate cell suspensions were plotted. In conclusion all findings indicated that the enzyme responsible for O-demethylation of CD, CYP2D1 was also responsible for the O-deethylation of EM to M.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Etilmorfina/metabolismo , Hígado/enzimología , Oxigenasas de Función Mixta/metabolismo , Animales , Citocromo P-450 CYP2D6 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/deficiencia , Femenino , Masculino , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/deficiencia , Derivados de la Morfina/metabolismo , Ratas , Ratas WistarRESUMEN
An experimental rat model was used to study postmortem redistribution of amitriptyline (AMI). Two hours after a subcutaneous injection with 20 mg of amitriptyline, the rats (n = 40) were anaesthetized and blood samples were drawn from the femoral vein and the heart. The rats were then sacrificed by CO2 and left at room temperature for either 0.1, 1, 2, 5, 24, 48, or 96 h. Postmortem blood samples from the heart and the inferior vena cava, and tissue samples from the lungs, heart, liver, right kidney, thigh muscle, the wall of the abdominal vena cava and brain were analyzed by high performance liquid chromatography. A significant increase was observed within 2 h postmortem in heart blood and later also in blood from the inferior vena cava. At 96 h postmortem the concentration increase was 4.4 +/- 0.5-fold (P < 0.01) and 3.0 +/- 1.1-fold (P < 0.05) as compared to the antemortem values observed in heart blood and blood from the inferior vena cava, respectively (mean +/- SEM). In the lungs there was a fall in the concentration of AMI from 148 +/- 16.7 mumol/kg at 0.1 h to 49.1 +/- 7.8 mumol/kg at 96 h postmortem (P < 0.01). In the vessel wall of the abdominal vena cava there was also a significant fall in drug concentration, while in heart muscle and liver an increase in drug concentration was observed. In animals where the lungs were removed agonally (n = 7), the drug concentration in heart blood had increased significantly less at 2 h postmortem.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Amitriptilina/análisis , Pulmón/química , Cambios Post Mortem , Animales , Química Encefálica , Cromatografía Líquida de Alta Presión , Riñón/química , Hígado/química , Masculino , Músculos/química , Miocardio/química , Ratas , Ratas Wistar , Distribución Tisular , Vena Cava Inferior/químicaRESUMEN
The biotransformation of morphine was characterized in freshly isolated parenchymal and non-parenchymal liver cells from rats and guinea pigs in suspension culture to establish an in vitro model for morphine metabolism. Liver cells were prepared by a collagenase perfusion technique, and separated by differential centrifugation. Morphine metabolism was investigated at different concentrations (1, 5, 100 and 200 microM). Samples were taken repeatedly during 2-4 hr of incubation, and subsequently analysed on a HPLC system employing both UV and electrochemical detection. In suspensions of hepatocytes from both animal species morphine-3-glucuronide (M3G) was the major metabolite of morphine, and was formed at comparable rates at all concentrations examined. Guinea pig hepatocytes in addition produced considerable quantities of morphine-6-glucuronide (M6G), whereas this metabolite was detected only intracellularly in minor quantities in rat hepatocytes. The ratio between the two morphine glucuronides (M3G/M6G) in suspensions of guinea pig hepatocytes was approximately 4:1. N-Demethylation of morphine was more pronounced per mg cell protein in rat hepatocytes compared to guinea pig cells. Metabolic activity towards morphine was not detected in non-parenchymal cells of the two species. The morphine glucuronidation pattern found in guinea pig hepatocytes resembles to a greater extent than that found in rat hepatocytes the pattern found in in vivo studies of humans. It was concluded that isolated guinea pig parenchymal cells appeared to be a promising in vitro system for studies of morphine glucuronidation, and to observe metabolism in general.
Asunto(s)
Hígado/metabolismo , Morfina/metabolismo , Animales , Biotransformación , Células Cultivadas , Glucuronatos/metabolismo , Cobayas , Masculino , Derivados de la Morfina/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The metabolism of ethylmorphine has been studied in suspensions of isolated rat hepatocytes. Early during incubation, the two major metabolic intermediates detected were morphine and norethylmorphine following N- and O-dealkylation of ethylmorphine, respectively. During subsequent incubation the concentration of the second metabolic intermediate, normorphine increased, before the concentration peaked at approximately 20 microM (100 microM ethylmorphine). Both morphine and normorphine were glucuronidated to form morphine-3-glucuronide and normorphine-3-glucuronide, respectively, which appeared to be the major metabolic end products. The percentage of ethylmorphine metabolized to morphine-3-glucuronide was found to be dependent on the initial concentration of ethylmorphine. With increasing initial ethylmorphine concentration the relative formation of morphine-3-glucuronide was reduced (29 +/- 10% at 5 microM, 18 +/- 5% at 20 microM, and 15 +/- 4% at 100 microM mean +/- S.D., n = 10). The concentrations of ethylmorphine and its metabolites were found to be higher in liver cells than in medium. Thus the ratios between the intra-/extra-cellular concentrations of ethylmorphine increased somewhat from an initial value of 4 during the period for which ethylmorphine could be detected intracellularly. The drug metabolites all exhibited ratios above 10 for the initial 100 min. of incubation. With time these ratios showed a decline, but even for prolonged incubation the ratios were 5 or higher for the end products. Thus considerable drug concentration gradients existed across the cell membrane of isolated rat hepatocytes.
Asunto(s)
Etilmorfina/metabolismo , Hígado/metabolismo , Animales , Células Cultivadas , Cromatografía Líquida de Alta Presión , Masculino , Derivados de la Morfina/metabolismo , Ratas , Ratas WistarRESUMEN
An experimental rat model was developed to study postmortem changes of drug concentration after an acute overdose. Overnight fasted rats were fed 75 mg of amitriptyline (AMI). Two h after dosing, the rats were anaesthetized and blood samples were drawn from the femoral vein (peripheral blood--PB) and the heart (HB). The rats were sacrificed by CO2 and left at room temperature for either 0.1, 0.5, 1, 2, 5, 10, 24, 48, or 96 hours, when samples of heart blood, blood from the inferior vena cava (PB) and tissue samples from different liver lobes, heart, lungs, kidney, thigh muscle, and brain were taken. Samples were analyzed by high performance liquid chromatography. The AMI concentration in HB increased fairly rapidly within the first 2 h postmortem and from then the average ratio was 6.4 +/- 0.8 (mean +/- sem) (n = 31). In PB, the post/antemortem AMI concentration ratio followed an approximately exponential rise; at 2 h postmortem the ratio was 1.6 +/- 0.3 (n = 5), and at 96 h 55.1 +/- 23.8 (n = 4). For the main metabolite nortriptyline (NOR), the concentration changes followed the same pattern, but to a lesser extent. Among the tissues, the liver lobes had high, but variable drug concentrations; lobes lying closest to the stomach had the highest drug concentrations. The drug concentration in the lungs declined significantly. This animal model demonstrates postmortem drug concentration changes similar to those described in humans. Probable mechanisms include drug diffusion from the stomach and GI tract to the surrounding tissues and blood; and postmortem drug release from the lungs and possibly other drug-rich tissues into the blood.
Asunto(s)
Amitriptilina/farmacocinética , Modelos Animales de Enfermedad , Cambios Post Mortem , Amitriptilina/envenenamiento , Animales , Sobredosis de Droga , Hígado/química , Pulmón/química , Masculino , Nortriptilina/sangre , Ratas , Ratas Wistar , Distribución TisularRESUMEN
Chronic ethanol consumption is associated with increased incidence of a variety of illnesses, including cancer. Studies have shown that ethanol consumption may result in increased oxidative stress with formation of lipid peroxides and free radicals. The susceptibility of a given tissue to peroxidation is, however, a function of the overall balance between prooxidants and antioxidant defence systems. The latter involve both intracellular and extracellular protective factors were nutrients play an important role. Impaired nutritional status of different vitamins and trace elements have been reported in alcoholics. Reduced levels of vitamin E have been found in serum of alcoholics with and without liver disease and in liver biopsies from alcoholics with cirrhosis. These findings may be due to the increased oxidative stress as reported in experimental animals, and may be of importance since vitamin E is the major, if not the only, lipid-soluble free radical scavenger in some tissues. Reduced antioxidant capacity has been found in several tissues and may promote the generation of free radicals and lipid peroxides which may damage cells directly, induce inflammation and accelerate collagen synthesis. These events may progress to tissue damage and disease. The importance of radicals in cancer initiation and promotion is presently of great interest. The role of lipid peroxides and free radicals in alcohol-related disease and cancer remains unresolved. Further research is required to establish the role of these reactive species in the pathogenesis of alcohol-related disease, and to evaluate the role of nutrition in favour of the antioxidant defence mechanisms.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Alcoholismo/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Especies Reactivas de Oxígeno , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Antioxidantes/metabolismo , Radicales Libres , Humanos , Peroxidación de Lípido/fisiología , Hepatopatías Alcohólicas/fisiopatología , Neoplasias/fisiopatología , Factores de RiesgoRESUMEN
A 48-year old woman died six days after intake of an unknown amount of trimethyltin (TMT). Early clinical features were tinnitus, lightheadedness, aggression and episodes of unresponsiveness. She gradually developed coma and died of multiorgan failure. The main pathologic findings were confined to the nervous system which revealed generalized chromatolysis of the neurons in the brain, spinal cord and spinal ganglia. Recent neuronal necrosis, which probably was caused by toxic effect of TMT, was present in the fascia dentata of the hippocampus and in the spinal ganglia. Recent necrosis was also present in the pyramidal cell layer of the hippocampus, cerebral cortex, basal ganglia and Purkinje cell layer of the cerebellum, but some of these changes could have been caused by an anoxic episode shortly before death. Electron microscopy revealed marked accumulation of lysosomal dense bodies and disorganization of the granular endoplasmic reticulum in the neurons. The findings were similar to those described in experimental TMT intoxications. Cytoplasmic zebra bodies, which were described in a previous human case of TMT intoxication, were not observed in the present case.
Asunto(s)
Compuestos de Trimetilestaño/envenenamiento , Autopsia , Encéfalo/patología , Encéfalo/ultraestructura , Femenino , Humanos , Microscopía Electrónica , Persona de Mediana Edad , Compuestos de Trimetilestaño/análisis , Compuestos de Trimetilestaño/orinaAsunto(s)
Diazepam/farmacocinética , Flunitrazepam/farmacocinética , Tiempo de Reacción/efectos de los fármacos , Adulto , Conducta de Elección , Diazepam/sangre , Diazepam/farmacología , Método Doble Ciego , Etanol/sangre , Etanol/farmacología , Flunitrazepam/sangre , Flunitrazepam/farmacología , HumanosRESUMEN
We determined the concentrations of ethanol in nearly simultaneous specimens of venous blood (BAC) and end-expired breath (BrAC) after healthy volunteers drank moderate amounts of alcohol. BAC was measured at two laboratories and BrAC was analyzed with two instruments (Intoxilyzer 5000) from the same manufacturer. The mean difference in BAC between laboratories was 0.0105 mg/g (SD 0.0219); 95% of the differences ranged from -0.0333 to 0.0543 mg/g. The mean difference in BrAC between instruments was 0.0153 mg/L (SD 0.0136), and 95% of the differences ranged from -0.0119 to 0.0425 mg/L. The coefficient of variation (CV) between laboratories was 2.9% compared with 4.5% between breath-test instruments. Venous BAC (y) and BrAC (x) were highly correlated (r = 0.978). However, when the Intoxilyzer instruments indicated that BrAC had reached zero, the actual BAC was 0.135 mg/g, according to the average forensic laboratory reports. The Intoxilyzer 5000 breath analyzers used in this study seem to have a constant analytical bias.
Asunto(s)
Pruebas Respiratorias/instrumentación , Etanol/análisis , Medicina Legal , Laboratorios/normas , Adulto , Etanol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega , Control de Calidad , SueciaRESUMEN
In some cases of drug overdose there is a reservoir of unabsorbed drug in the stomach and gut. Furthermore, agonal aspiration might establish a second reservoir in the lungs. Two experimental rat models were used to study if diffusion from these reservoirs could contribute to the phenomenon of postmortem drug redistribution. Overnight fasted rats were sacrificed by CO2 and 75 mg of amitriptyline (AMI) was administered by a gastric tube. In the first series (n = 19), the tubes were removed after AMI administration. In the second series (n = 17), the trachea was ligated and cut prior to drug administration to prevent airways contamination. The rats were left at room temperature on their back for a period of 5, 10, 24, 48, 96 up to 192 h and samples of heart blood, blood from the inferior vena cava, tissue samples from heart, lungs, different liver lobes, kidney and psoas muscle were taken. In both series of rats we observed that as early as 5 h postmortem increasing concentrations of amitriptyline were found in the liver lobes lying closest to the stomach. In rats where the trachea was not ligated, drug contamination of the lungs also resulted in an increase in drug concentration within 5 h in heart blood and heart muscle. In rats where the trachea had been ligated, amitriptyline was found in the lungs after 96 h postmortem. The main metabolite nortriptyline was also detected.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Amitriptilina/envenenamiento , Medicina Legal/métodos , Intoxicación/metabolismo , Cambios Post Mortem , Amitriptilina/química , Amitriptilina/farmacocinética , Animales , Estudios de Evaluación como Asunto , Medicina Legal/normas , Riñón/química , Hígado/química , Pulmón/química , Masculino , Miocardio/química , Intoxicación/sangre , Músculos Psoas/química , Ratas , Ratas Endogámicas , Factores de Tiempo , Distribución Tisular , Tráquea/cirugíaRESUMEN
The effects of acute arterial subdural bleeding on cerebrospinal fluid (CSF) pressure and 12 other vital parameters were studied in spontaneously breathing pigs (group 1, n = 9) and in mechanically ventilated pigs (group 2, n = 18) to analyze quantitatively the bleeding course and the lethal mechanism. Spontaneously breathing animals all succumbed after a mean bleeding volume of 45.6 +/- 8.9 ml, corresponding to about 50 per cent of the intracranial volume, and a mean bleeding duration of 11.0 +/- 2.6 min. Rapid rise in CSF pressures, marked transtentorial pressure gradients, and progressive reductions of cerebral perfusion pressure leading to a permanently iso-electric EEG, apnoea and to a terminal rise in arterial pressure (Cushing response), was the rule in these animals. The mechanically ventilated animals had smaller bleeding volumes (34.3 +/- 8.1 ml), but longer bleeding durations (13.8 +/- 5.8 min). In this group 7 animals survived. They had no pressure gradients, and only moderate changes in arterial pressure and EEG. The 11 animals that succumbed had marked transtentorial pressure gradients, but smaller increments in arterial pressure than the spontaneously breathing animals. At autopsy, subdurally located blood was found throughout the intracranial and spinal subdural compartments and along the spinal nerve roots in both groups. The results of this study suggest that survival after acute subdural haematoma is influenced by the presence of transtentorial pressure gradients and by the spinal sac acting as a space for expansion. The beneficial effect of artificial ventilation is discussed.
Asunto(s)
Presión del Líquido Cefalorraquídeo/fisiología , Modelos Animales de Enfermedad , Hematoma Subdural/fisiopatología , Animales , Encéfalo/patología , Perros , Encefalocele/patología , Encefalocele/fisiopatología , Hematoma Subdural/patología , Homeostasis/fisiología , Presión Intracraneal/fisiología , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Respiración/fisiología , Médula Espinal/patología , PorcinosRESUMEN
In a placebo controlled, crossover study psychomotor effects of single doses of diazepam, 10 and 20 mg, flunitrazepam, 1 and 2 mg, as well as 0.9 g ethanol/kg body weight were investigated over a time period of 6 h in 12 healthy men. Blood samples were collected simultaneously with the test sessions to determine drug concentrations in plasma or blood. The ethanol dose caused the least performance impairment, followed by 10 mg diazepam. The most pronounced impairment was caused by 2 mg flunitrazepam, whereas 20 mg diazepam and 1 mg flunitrazepam caused intermediate impairment and were approximately equipotent on group level. Considerable interindividual differences with respect to maximal impairment following a particular drug treatment were observed, with poor correlation between individual maximal impairments and individual peak plasma concentrations of the drug. The maximal impairment in simple reaction time following the flunitrazepam treatments occurred earlier relative to the peak plasma concentration of the drug as compared to the diazepam treatments. This may indicate that acute tolerance develops differently for the two drugs.
Asunto(s)
Diazepam/farmacología , Etanol/farmacología , Flunitrazepam/farmacología , Desempeño Psicomotor/efectos de los fármacos , Adulto , Análisis de Varianza , Diazepam/sangre , Método Doble Ciego , Etanol/sangre , Flunitrazepam/sangre , Humanos , Masculino , Tiempo de Reacción/efectos de los fármacos , Sueño/efectos de los fármacosRESUMEN
The concentration of alpha-tocopherol was measured in liver biopsy specimens obtained from 83 patients with alcoholic and non-alcoholic liver diseases. The mean hepatic vitamin E content (as alpha-tocopherol) was significantly lower in 23 patients with alcoholic cirrhosis (17.6 +/- 12.1 nmol/mg wet weight liver), compared with 12 patients with normal liver histology (39.2 +/- 29.7 nmol/mg, P less than 0.01). The mean serum concentration of alpha-tocopherol was lower in patients with alcoholic cirrhosis (13.9 +/- 7.0 mumol/l) than in individuals with alcoholic fatty liver (21.3 +/- 9.3 mumol/l, P less than 0.01) and patients with normal liver histology (23.4 +/- 11.6 mumol/l, P less than 0.01). A decreased ratio of serum alpha-tocopherol/total serum lipids was also observed in patients with alcoholic cirrhosis, compared with patients with normal liver histology (P less than 0.05). There was a significant correlation between concentrations of alpha-tocopherol in liver and serum (r = 0.43, P less than 0.001). Furthermore, serum alpha-tocopherol correlated with retinol (r = 0.53, P less than 0.001), selenium (r = 0.45, P less than 0.001), and albumin (r = 0.37, P less than 0.001) in serum. We suggest that the reduced content of hepatic alpha-tocopherol observed in some patients may play a role in ethanol-induced lipid peroxidation.